Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 6, Pages 3730-3739Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.030460
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Funding
- Deutsche Forschungsgemeinschaft [BE1138/5-3]
- Elitenetzwerk Bayern [K-BM-200385]
- Medical Research Council [G0500833, G0501258, G0601585]
- European Framework Program 7 [HEALTH-F4-2008-202088]
- Medical Research Council [G0601585, G0501258, G0500833] Funding Source: researchfish
- MRC [G0501258, G0601585, G0500833] Funding Source: UKRI
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The strychnine-sensitive glycine receptor (GlyR) is a ligand-gated ion channel that mediates fast synaptic inhibition in the vertebrate central nervous system. As a member of the family of Cys-loop receptors, it assembles from five homologous subunits (GlyR alpha 1-4 and -beta). Each subunit contains an extracellular ligand binding domain, four transmembrane domains (TM), and an intracellular domain, formed by the loop connecting TM3 and TM4(TM3-4 loop). The TM3-4 loops of the subunits GlyR alpha 1 and -alpha 3 harbor a conserved basic motif, which is part of a potential nuclear localization signal. When tested for functionality by live cell imaging of green fluorescent protein and beta-galactosidase-tagged domain constructs, the TM3-4 loops of GlyR alpha 1 and -alpha 3, but not of GlyR alpha 2 and -beta, exhibited nuclear sorting activity. Subunit specificity may be attributed to slight amino acid alterations in the basic motif. In yeast two-hybrid screening and GST pulldown assays, karyopherin alpha 3 and alpha 4 were found to interact with the TM3-4 loop, providing a molecular mechanism for the observed intracellular trafficking. These results indicate that the multifunctional basic motif of the TM3-4 loop is capable of mediating a karyopherin-dependent intracellular sorting of full-length GlyRs.
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